ifinatamab deruxtecan (DS-7300)

P1/2, N=250, Recruiting, Daiichi Sankyo | Trial primary completion date: Dec 2024 --> Dec 2025

P1/2, N=450, Recruiting, Merck Sharp & Dohme LLC | Active, not recruiting --> Recruiting

P3, N=510, Not yet recruiting, Daiichi Sankyo

P1/2, N=450, Active, not recruiting, Merck Sharp & Dohme LLC | Phase classification: P2 --> P1/2

P1/2, N=149, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P2, N=520, Recruiting, Daiichi Sankyo | N=260 --> 520 | Trial primary completion date: Dec 2026 --> Jul 2028

P1/2, N=232, Recruiting, Harpoon Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | N=162 --> 232 | Trial primary completion date: Jul 2025 --> Jan 2026

Although toxicities exceeding expectations have been observed with Rova-T, drugs targeting TROP-2 (Sacituzumab Govitecan), B7-H3 (DS-7300), and SEZ6 (ABBV-011) have shown exciting clinical benefits. In this review, we collect the latest clinical evidence to describe the therapeutic efficacy and safety of ADCs in SCLC and discuss prospects and challenges.

P3, N=468, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P2, N=187, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

Nivolumab and pembrolizumab are anti-PD-1 antibodies that improve immunosuppression by binding to programmed death-1 (PD-1), leading to an antitumor effect...Sym004 and amivantamab are antibodies that target the epidermal growth factor receptor and have demonstrated efficacy in the treatment of other tumors in recent phase I studies. Furthermore, clinical trials on antibody-drug conjugates such as enfortumab vedotin and DS-7300 for solid tumors are currently ongoing. The standard first-line treatments for patients with advanced ESCC contain ICIs. Therefore, drugs with different mechanisms of action that can overcome resistance to ICIs are needed as second-line or later-line treatments to improve clinical outcomes in these patients.

P3, N=468, Not yet recruiting, Daiichi Sankyo | Trial completion date: Jan 2028 --> Feb 2029 | Trial primary completion date: Jul 2026 --> Apr 2027

P2, N=260, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P1/2, N=149, Not yet recruiting, Daiichi Sankyo

P2, N=260, Not yet recruiting, Daiichi Sankyo

P2, N=180, Recruiting, Daiichi Sankyo | N=91 --> 180 | Trial completion date: Nov 2024 --> Jul 2025 | Trial primary completion date: May 2024 --> Jan 2025

P2, N=91, Recruiting, Daiichi Sankyo, Inc. | Active, not recruiting --> Recruiting

P3, N=468, Not yet recruiting, Daiichi Sankyo, Inc.

Despite the negative results of rovalpituzumab tesirine (Rova-T), other ADCs targeting different antigens, such as B7-H3, seizure-related homolog 6 (SEZ6), and CEACAM5, have also been investigated in clinical trials, including for SCLC, and their results suggest preliminary activity, either alone or in combination with other therapies. More recently, sacituzumab govitecan, an anti-TROP2 ADC, demonstrated promising activity in lung cancer, including SCLC. Furthermore, an anti-B7-H3 (CD276), ifinatamab deruxtecan (DS7300A), showed a high response rate and durable responses in heavily pretreated SCLC...Further studies are needed to determine their efficacy and safety and the best location in the treatment algorithm for SCLC. In this review, we aim to collect and describe the results regarding the past, the present, and the future of ADCs in SCLC.

Decitabine, a pan-DNMT inhibitor, attenuated tumor growth in NEPC patient-derived xenograft models, as well as retinoblastoma gene (RB1)-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1-proficient CRPC. DNMT inhibition may therefore be a promising therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis, and the development of biomarker-driven therapeutic strategies for these populations may ultimately help improve patient outcomes.

Multiple anti-B7-H3 therapies has been raised, such as DS-7300, MGA271, MGD009, and B7-H3 chimeric antigen receptor T-cell immunotherapy (CAR-T)...In the durvalumab-dependent cohort, paclitaxel-dependent cohort, anthracycline-dependent cohort, and our recruited NAT cohort, the B7-H3highPDL1low subgroup exhibited the lowest therapeutic response. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression that could potentially be applied to predict the therapeutic responses in TNBC, and suggests a potential biomarker-guided anti-B7-H3 therapy. Based on the classifier, we can select potential beneficiaries to deliver personalized medical services.

The addition of an anti-PD-L1, atezolizumab or durvalumab, to platinum/etoposide regimen became the standard of care for first-line therapy of extensive-stage (ES)-SCLC with the 12 months median survival exceeded for the first time. The most promising preliminary clinical results have been reported by DS7300a and HS-20093, both are antibody-drug conjugates, that are under investigation in ongoing trials for the treatment of pretreated SCLC. This review will provide an overview of B7-H3 and corresponding inhibitors and the clinical development in the management of SCLC.

B7-H3 expression was moderate to high in most patients; no correlation was observed between response and B7-H3 level, and an update will be presented at the congress. Table: 690P Efficacy Conclusions I-DXd continues to demonstrate a manageable safety profile and promising antitumor activity with encouraging DOR and OS in these heavily pretreated patients, which warrants further clinical evaluation across multiple indications.

Other parameters being measured include safety, pharmacokinetics, exposure-response, immunogenicity, and biomarkers. The estimated study completion date is November 2024.

I-DXd demonstrated robust and durable efficacy in this subset of patients with heavily pretreated SCLC. Likewise, it was tolerable with manageable toxicity. A phase 2 study (NCT05280470) of patients with second- or third-line extensive stage SCLC only is currently ongoing.

P2, N=91, Active, not recruiting, Daiichi Sankyo, Inc. | Recruiting --> Active, not recruiting

In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC.

P2, N=140, Ongoing, Daiichi Sankyo, Inc.

The frequent overexpression of B7-H3 in CRPC compared with normal tissue and other B7 family members implicates it as a highly relevant therapeutic target in these diseases. Mechanisms driving differences in B7-H3 expression across genomic subsets warrant investigation for understanding the role of B7-H3 in cancer growth and for the clinical development of B7-H3 targeted therapies.

Conclusions DS-7300 continues to demonstrate evidence of durable antitumor activity in heavily pretreated pts with SCLC, sqNSCLC, and mCRPC. These data support further clinical development of DS-7300, including a Ph 2 dose-optimization study in SCLC (NCT05280470) with starting dose levels of 8 mg/kg and 12.0 mg/kg.

P2, N=80, Recruiting, Daiichi Sankyo, Inc. | Trial completion date: Jun 2024 --> Nov 2024 | Trial primary completion date: Oct 2023 --> May 2024

P2, N=80, Recruiting, Daiichi Sankyo, Inc. | Not yet recruiting --> Recruiting

DS-7300a exerted potent antitumor activities against B7-H3-expressing tumors in in vitro and in vivo models including PDX mouse models and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3-expressing solid tumors in a clinical setting.

P2, N=80, Not yet recruiting, Daiichi Sankyo, Inc.

DS-7300 was well tolerated with an acceptable safety profile in pts with mCRPC. The preliminary safety and efficacy data are encouraging and warrant further investigation.

DS-7300 was generally well tolerated with early signs of clinical activity, including objective responses, in pts with pretreated advanced solid tumors. Expansion cohorts are currently enrolling to evaluate DS-7300 in selected tumor types.